Inclusion Criteria:

• Metastatic or locally advanced (unresectable) colorectal cancer with histological confirmation of adenocarcinoma.
• Age ≥18 years of age. Note: Because no dosing or adverse event data are currently available on the use of cetuximab or bevacizumab in subjects <18 years of age, children are excluded from this study.
• Measurable disease as defined in Section 11.0.
• KRAS wild-type tumor (codons 12 and 13).

Note: Evidence of EGFR expression in the tumor is not required.

Note: Although testing for other RAS mutations is not required, a known mutation in other regions of KRAS, NRAS, or HRAS is exclusionary.

- Previous failure of at least one fluoropyrimidine- and irinotecan-containing chemotherapy regimen for metastatic disease.

Note: Previous failure is defined as disease progression while receiving treatment or within 6 weeks after the last dose of irinotecan. Failure for this assessment is defined as any enlargement of measurable or assessable lesion(s) or the development of any new lesion. A rising tumor marker alone is not sufficient to define failure. Patients can have received irinotecan in any previous line of therapy.

• Treatment with bevacizumab in at least one prior line of therapy for metastatic disease.
• Negative serum or urine pregnancy test done ≤7 days prior to registration, for women of childbearing potential only.

Note: Childbearing potential is defined as a female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who is not postmenopausal (defined as amenorrhea ≥12 consecutive months; or women on hormone replacement therapy with documented serum follicle stimulating hormone level >35 mIU/mL). Women who are using oral, implanted, or injectable contraceptive hormones or mechanical products such as intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or who are practicing abstinence or where partner is sterile (e.g., vasectomy), should be considered to be of childbearing potential.

• ECOG Performance Status (PS): 0 or 1 (form available on the ACCRU member website at https://www.accru.org/accru/forms/NonProtocolSpecificForms/index.html).
• Adequate organ and bone marrow function as defined below (see Section 3.19b)
• The following laboratory values obtained ≤14 days prior to randomization.
• Total serum bilirubin ≤ institutional upper limit of normal (ULN)
• Absolute neutrophil count (ANC) ≥1500/mm3
• Platelet count >100,000/mm3
• Hemoglobin ≥9.0 g/dL (hemoglobin may be supported by transfusion)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer)
• Creatinine within institutional limits of normal OR
• creatinine clearance >60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
• Urinary protein ≤ 1+
• Patients discovered to have ≥2+ proteinuria must have a spot urine protein:creatinine ratio (UPCR) <1.0
• Partial thromboplastin time (PTT) ≤1x institutional ULN and international normalized ratio (INR) ≤1.5, unless participant is on full dose anticoagulation therapy. Patients on full-dose anticoagulation are eligible if the following criteria are met:
• Patient has an in-range INR (usually 2-3) on a stable dose of warfarin ≤ 14 days or is on a stable dose of low molecular weight heparin
• Patient has no active bleeding or pathological condition that carries a high risk of bleeding (i.e., tumor involving major vessels or known varices)
• Patients receiving anti-platelet agents are eligible. In addition, patients who are on daily prophylactic aspirin or anticoagulation for atrial fibrillation are eligible.
• Life expectancy >3 months.
• Willing to provide tissue and blood samples for mandatory correlative and research purposes (see Sections 6.0, 14.0 and 17.0).
• Any major surgery or open biopsy completed ≥4 weeks prior to randomization.
• Any minor surgery or core biopsy completed ≥1 week prior to randomization and patient must have fully recovered from the procedure.

Note: Insertion of a vascular access device is not considered major or minor surgery.

Exclusion Criteria:

• Presence of any RAS mutation
• Prior treatment with cetuximab or panitumumab.
• Prior intolerance to irinotecan and/or bevacizumab despite dose reduction.
• Known or suspected brain or central nervous system (CNS) metastases, or carcinomatous meningitis.

Note: Participants with brain or CNS metastases are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

• Active, uncontrolled infection, including hepatitis B, hepatitis C.
• Concurrent anti-cancer therapy, including chemotherapy agents, targeted agents, or biological agents not otherwise specified in this protocol.
• Anti-cancer therapy ≤14 days prior to randomization.
• Prior radiotherapy to >25% of bone marrow.

Note: Standard rectal cancer chemoradiation will not exclude subject from study protocol.

• Radiation therapy ≤2 weeks prior to randomization.
• Any of the following, because this study involves agents whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
• Pregnant women
• Nursing women
• Men or women of childbearing potential who are unwilling to employ adequate contraception
• Co-morbid systemic illnesses or other severe concurrent disease, history of any psychiatric or addictive disorder, or laboratory abnormality, which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Patients known to be HIV positive

Note: HIV-positive individuals on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with irinotecan, cetuximab, and bevacizumab. In addition, these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, symptomatic pulmonary fibrosis or interstitial pneumonitis, or psychiatric illness/social situations that, in the opinion of the investigator, may increase the risks associated with study participation or study treatment, or may interfere with the conduct of the study or the interpretation of the study results.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• Other active malignancy ≤3 years prior to registration.

EXCEPTIONS: Non-melanoma skin cancer, prostatic intraepithelial neoplasia without evidence of prostate cancer, lobular carcinoma in situ in one breast, or carcinoma-in-situ of the cervix that has been treated.

• History of prior malignancy for which patient is receiving other specific treatment for their cancer.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to irinotecan, cetuximab, and/or bevacizumab that led to discontinuation of those agents.
• Significant history of bleeding events or pre-existing bleeding diathesis ≤6 months of randomization (unless the source of bleeding has been resected)
• History of gastrointestinal perforation ≤12 months prior to randomization.

3.29l Predisposing colonic or small bowel disorders in which the symptoms are uncontrolled as indicated by baseline pattern of >3 loose stools daily in subjects without a colostomy or ileostomy. Subjects with a colostomy or ileostomy may be entered at investigator discretion.

• Arterial thrombotic events ≤6 months prior to randomization Note: This includes transient ischemic attack (TIA), cerebrovascular accident (CVA), unstable angina or angina requiring surgical or medical intervention in the past 6 months, or myocardial infarction (MI).
• Clinically significant peripheral artery disease (e.g., claudication with <1 block) or any other arterial thrombotic event.
• Serious or non-healing wound, ulcer, or bone fracture.
• History of hypertension not well-controlled (≥160/90) even though on a regimen of anti-hypertensive therapy.
• Evidence of Gilbert's syndrome or known homozygosity for the UGT1A1*28 allele (special screening not required).